Bede Portz

dimenwarper Verified account @tsuname · Nov 3

>be cell biology postdoc at UCLA, 1986
>job: purify vesicles from rat liver
>ez
>purify the vesicles
>something else in the tube
>weird little barrels, way bigger than a ribosome
>fkisdis
>purify the barrels instead
>mostly protein, tiny bit of RNA
>not related to vesicles at all
>new organelle just dropped?
>lab holds a naming contest
>"vaults" "sure, "great name" "
>write it up, publish
>conclusion section: "function: unknown"
>surely we'll figure it out in a couple years
>reviewers: "are you sure this isn't just a virus"
>prove it isn't a virus
>apply for grants to study it
>first question on every call: "what does it do"
>"we're working on it"
>be early 90s
>vaults hang around the nucleus
>"they must plug the nuclear pores"
>they do not
>be different scientist, Netherlands, 1995
>chasing LRP, mystery protein that shows up in chemo-resistant tumors
>clone it
>~88% identical to rat vault protein
>it was vaults the whole time
>whole cancer field piles on
>a decade of papers on vaults and drug resistance
>nobody ever proves vaults cause it
>back at UCLA
>one of the vault proteins binds telomerase
>"guys what if this is the fountain of youth"
>knock it out in mice
>telomeres fine, aging fine, mice fine
>2002
>knock out the main vault protein
>mice: perfectly healthy
>knock out all three vault proteins
>completely vaultless mice
>mice: basically fine, some subtle immune stuff
>mfw something in every cell since the dawn of eukaryotes does nothing obvious
>"just test it in yeast"
>yeast don't have vaults
>"worms then"
>no vaults
>"fruit flies"
>no vaults
>mfw every easy model organism dropped them
>try making recombinant vaults in insect cells
>expecting to get some loose protein at best
>get fully assembled vaults
>can't find a single free copy of the protein anywhere
>turns out ribosomes 3D-print the barrel straight off the mRNA
>lolwut
>still no function
>be structural biologists
>spend years modeling it as 96 proteins with 8-fold symmetry
>2009 X-ray structure
>it's 78 proteins, 39-fold
>caps still blurry
>2025: caps are closed, 13-fold, tiny hole in the middle
>still no function
>NIH funds vault research for 15 years
>NIH: "so what does it do"
>"...we're working on it"
>NIH stops returning calls
>if we can't figure out what it does, we'll make it do something
>stuff a cancer-fighting chemokine inside the barrel
>inject into mouse lung tumors
>immune cells swarm in, tumors shrink
>2011: "human trials within three years"
>2024: "human trials next year"
>2025 database: preclinical
>start a YouTube channel explaining vaults to anyone who'll listen
>be different scientist, Broad Institute
>want to record what genes a cell turned on over time
>try tethering mRNA to a bacterial protein
>doesn't work
>stumble onto a YouTube channel about some obscure barrel organelle
>engineer vaults to grab mRNA
>RNA half-life goes from ~17 hours to ~132 hours
>publish in Science, 2026
>use it to catch drug-resistance genes in lung cancer cells before the drug even hits
>the vault guy is thrilled
>still nobody knows what vaults are for
>be epigeneticists
>screen the whole genome for methylation set at random in the early embryo
>separately study kids conceived in different seasons in rural Gambia
>both screens independently point at the same gene
>it's the goddam vault RNA gene
>its methylation depends on conditions around conception, locked in for life
>linked to cancer outcomes, blood sugar, cleft palate
>mfw the mystery barrel has a mystery RNA that remembers when you were conceived
>40 years later
>one of the most abundant structures in your cells
>still not in a single textbook cell diagram
>we use it anyway because yolo
>function: unknown

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